We report five new spectral variants of bright luminescent protein made by concatenation of the brightest luciferase,
NanoLuc, with various color hues of fluorescent proteins. These proteins, which we call enhanced Nano-lanterns (eNLs),
allow five-color live-cell imaging without external light illumination as well as detection of single molecules.
Furthermore, eNL-based Ca2+ indicators could be used to image long-term Ca2+ dynamics in iPS-derived cardiomyocytes.

Light delivery in in vivo optogenetic applications are typically accomplished via a single multimode fiber that diffuses light over a large area of the brain, and relies heavily on the spatial distribution of transfected light-sensitive neurons for targeted control.
In our investigations, an imaging fiber bundle (Schott, 1534702) containing 4,500 individual fibers, each with a diameter of 7.5 µm, and an overall outer bundle diameter of 530 µm, was used as the conduit for light delivery and optical recording/imaging in neuron cultures and in in vivo mouse brain. We demonstrated that the use of this fiber bundle, in contrast to a single multimode fiber, allowed for individually-addressable fibers, spatial selectivity at the stimulus site, precise control of light delivery, and full field-of-view imaging and/or optical recordings of neurons. An objective coupled the two continuous wave diode laser sources (561 nm/488 nm) for stimulation and imaging into the proximal end of the fiber bundle while a set of galvanometer-scanning mirrors was used to couple the light stimulus to distinct fibers. A micro lens aided in focusing the light at the neurons. In vivo studies utilized C1V1(E122T/E162T)-TS-p2A-mCherry (Karl Deisseroth, Stanford) and GCaMP6s transgenic mice (Jackson Labs) for this all-optical approach.
Our results demonstrate that imaging fiber bundles provide superior control of spatial selectivity of light delivery to specific neurons, and function as a conduit for optical imaging and recording at the in vivo site of stimulation, in contrast to the use of single multimode fibers that diffusely illuminate tissue and lack in vivo imaging capabilities.

As the optogenetic field expands its need to target with high specificity only grows more crucial. This work will show a method for customizing soda-lime glass optrode arrays so that fine structures within the brains of small rodents and nonhuman primates can be optically interrogated below the outer cortical layer. An 8 × 6 array is customized for optrode length (400 μm ), optrode width (75 μm ), optrode pitch (400 μm ), backplane thickness (500 μm ), and overall form factor (3.45 mm × 2.65 mm ). The 400 μm long optrode is capable of illuminating the cortical Layer IV of rhesus macaque ( Macaca Fascicularis ) and the motor cortex of small mice ( Mus Musculus ).

Electrophysiology techniques are the gold standard in neuroscience for studying functionality of a single neuron to a complex neuronal network. However, electrophysiology techniques are not flawless, they are invasive nature, procedures are cumbersome to implement with limited capability of being used as a high-throughput recording system. Also, long term studies of neuronal functionality with aid of electrophysiology is not feasible. Non-invasive stimulation and detection of neuronal electrical activity has been a long standing goal in neuroscience. Introduction of optogenetics has ushered in the era of non-invasive optical stimulation of neurons, which is revolutionizing neuroscience research. Optical detection of neuronal activity that is comparable to electro-physiology is still elusive. A number of optical techniques have been reported recording of neuronal electrical activity but none is capable of reliably measuring action potential spikes that is comparable to electro-physiology. Optical detection of action potential with voltage sensitive fluorescent reporters are potential alternatives to electrophysiology techniques. The heavily rely on secondary reporters, which are often toxic in nature with background fluorescence, with slow response and low SNR making them far from ideal. The detection of one shot (without averaging)-single action potential in a true label-free way has been elusive so far. In this report, we demonstrate the optical detection of single neuronal spike in a cultured mammalian neuronal network without using any exogenous labels. To the best of our knowledge, this is the first demonstration of label free optical detection of single action potentials in a mammalian neuronal network, which was achieved using a high-speed phase sensitive interferometer. We have carried out stimulation and inhibition of neuronal firing using Glutamate and Tetrodotoxin respectively to demonstrate the different outcome (stimulation and inhibition) revealed in optical signal. We hypothesize that the interrogating optical beam is modulated during neuronal firing by electro-motility driven membrane fluctuation in conjunction with electrical wave propagation in cellular system.

Monitoring brain activities in awake and freely moving status is very important in physiological and pathological studies
of brain functions. In this study, we developed a new standalone micro-device combining electrophysiology and optical
imaging for monitoring the cerebral blood flow and neural activities with more feasibility for freely moving animals.

Electrocorticography (ECoG) is a powerful tool for direct mapping of local field potentials from the brain surface. Progress in development of high-fidelity materials such as poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) on thin conformal substrates such as parylene C enabled intimate contact with cortical surfaces and higher quality recordings from small volumes of neurons. Meanwhile, stimulation of neuronal activity is conventionally accomplished with electrical microstimulation and transcranial magnetic stimulation that can be combined with ECoG to form the basis of bidirectional neural interface. However, these stimulation mechanisms are less controlled and primitively understood on the local and cellular levels. With the advent of optogenetics, the localization and specificity of neuronal stimulation and inhibition is possible. Therefore, the development of integrated devices that can merge the sensitivity of ECoG or depth recording with optogenetic tools can lead to newer frontiers in understanding the neuronal activity.
Herein, we introduce a hybrid device comprising flexible inorganic LED arrays integrated PEDOT:PSS/parylene C microelectrode arrays for high resolution bidirectional neuronal interfaces. The flexible inorganic LEDs have been developed by the metal-organic vapor phase epitaxy of position-controlled GaN microLEDs on ZnO nanostructured templates pre-grown at precise locations on a graphene layer. By transferring it onto the microelectrode arrays, it can provides the individual electrical addressability by light stimulation patterns. We will present experimental and simulation results on the optoelectronic characteristics and light activation capability of flexible microLEDs and their evaluation in vivo.

Electrical pacing is the current gold standard for investigation of mammalian cardiac electrical conduction systems as well as for treatment of certain cardiac pathologies. However, this method requires an invasive surgical procedure to implant the pacing electrodes. Recently, optogenetic pacing has been developed as an alternative, non-invasive method for heartbeat pacing in animals. It induces heartbeats by shining pulsed light on transgene-generated microbial opsins which in turn activate light gated ion channels in animal hearts. However, commonly used opsins, such as channelrhodopsin-2 (ChR2), require short light wavelength stimulation (475 nm), which is strongly absorbed and scattered by tissue. Here, we expressed recently engineered red-shifted opsins, ReaChR and CsChrimson, in the heart of a well-developed animal model, Drosophila melanogaster, for the first time. Optogenetic pacing was successfully conducted in both ReaChR and CsChrimson flies at their larval, pupal, and adult stages using 617 nm excitation light pulse, enabling a much deeper tissue penetration compared to blue stimulation light. A customized high speed and ultrahigh resolution OCM system was used to non-invasively monitor the heartbeat pacing in Drosophila. Compared to previous studies on optogenetic pacing of Drosophila, higher penetration depth of optogenetic excitation light was achieved in opaque late pupal flies. Lower stimulating power density is needed for excitation at each developmental stage of both groups, which improves the safety of this technique for heart rhythm studies.

Pulsed infrared (IR) light has been used in multiple animal models to inhibit neural activity. Duke et al.
reported inhibition associated with a temperature increase of ~8°C in Aplysia californica buccal nerve 2
(BN2). There is no evidence that the current irradiation schemes alters nerve functionality, however lower
temperatures provide a safer environment for sustained inhibition. Inhibition paradigms use a single optical
fiber to deliver IR light, resulting in a single hotspot within the nerve. One proposed method for decreasing
peak temperatures is to use a lower radiant exposure over a greater area, effectively heating the nerve more
evenly. Preliminary computational modeling suggests that using two axially adjacent optical fibers reduces
peak temperatures required for infrared neural inhibition (INI). This hypothesis is being validated in vitro in
Aplysia. Pleural abdominal nerves were dissected out, and suction electrodes were applied to electrically
stimulate and record neural activity. A custom probe (core diameters= 400 μm) was used to simultaneously
apply IR light from two diode lasers (Lockheed-Martin, λ=1875nm) to the nerve and monitor the radiant
exposure out of each. Radiant exposures required for inhibition using a single fiber were reduced by ~37.4%
by using two axially adjacent optical fibers. While mechanisms behind infrared inhibition are not fully
understood, data suggests that a threshold temperature is required. By reducing peak temperatures, neural
block using IR light will subject nerves to lower peak temperatures and provide a more research and clinically
relevant technology.

High spatiotemporal resolution deep-brain optical excitation for optogenetics would enable activation of specific neural populations and in-depth study of neural circuits. Conventionally, a single fiber is used to flood light into a large area of the brain with limited resolution. The scalability of silicon photonics could enable neural excitation over large areas with single-cell resolution similar to electrical probes. However, active control of these optical circuits has yet to be demonstrated for optogenetics.
Here we demonstrate the first active integrated optical switch for neural excitation at 473 nm, enabling control of multiple beams for deep-brain neural stimulation. Using a silicon nitride waveguide platform, we develop a cascaded Mach-Zehnder interferometer (MZI) network located outside the brain to direct light to 8 different grating emitters located at the tip of the neural probe. We use integrated platinum microheaters to induce a local thermo-optic phase shift in the MZI to control the switch output. We measure an ON/OFF extinction ratio of >8dB for a single switch and a switching speed of 20 microseconds. We characterize the optical output of the switch by imaging its excitation of fluorescent dye.
Finally, we demonstrate in vivo single-neuron optical activation from different grating emitters using a fully packaged device inserted into a mouse brain. Directly activated neurons showed robust spike firing activities with low first-spike latency and small jitter. Active switching on a nanophotonic platform is necessary for eventually controlling highly-multiplexed reconfigurable optical circuits, enabling high-resolution optical stimulation in deep-brain regions.

Optical manipulation of cellular functions represents a growing field in biomedical sciences. The possibility to modulate specific targets with high spatial and temporal precision in a contactless manner allows a broad range of applications. Here, we present a study on stimulation of neuronal cells by optical means. As a long-term objective, we seek to improve the performance of current electric neurostimulation, especially in the context of cochlear implants. Firstly, we tested a gold nanoparticle mediated approach to modulate transmembrane conductivity by irradiation using a picosecond pulsed Nd:YAG laser at 532 nm for 40 ms in a neuroblastoma cell line (N2A) and primary murine neurons. The light absorption leads to a rapid temperature increase of the gold nanoparticles, which can induce an increased permeabilisation of the cellular membrane. Calcium transients were recorded as an indicator of neuronal activity. Although calcium signals were reliably detected upon laser irradiation, the temporal behavior did not resemble action potentials. The origin of these signals was investigated by an inhibitor study. These results indicate calcium induced calcium release (CICR) as the major source of the calcium transients. Consecutively, we tested alternative approaches for cell stimulation, such as glutamate release and optogenetics, and evaluated the potential of these methods for the application in a cochlear implant. Compared to the gold nanoparticle approach, both techniques induce less cellular stress and reliably produce action potentials.

Optogenetic experiments require light delivery, typically using fiber optics, to light-gated ion channels genetically targeted to specific brain regions. Understanding where light is—and isn’t—in an illuminated brain can be a confounding factor in designing experiments and interpreting results. While the transmission of light, i.e. survival of forward-directed and forward–scattered light, has been extensively measured in vitro, light scattering can be significantly different in vivo due to blood flow and other factors. To measure irradiance in vivo, we constructed a pipette photodetector tipped with fluorescent quantum dots that function as a light transducer. The quantum dot fluorescence is collected by a waveguide and sent to a fiber-coupled spectrometer. The device has a small photo-responsive area (~ 10 um x 15 um), enabling collection of micron-resolution irradiance profiles, and can be calibrated to determine irradiance with detection limits of 0.001 mW/mm2. The photodetector has the footprint of a micro-injection pipette, so can be inserted into almost any brain region with minimal invasiveness. With this detector, we determined transverse and axial irradiance profiles in mice across multiple brain regions at 5 source wavelengths spanning the visible spectrum. This profile data is compared to in vitro measurements obtained on tissue slices, and provides a means to derive scattering coefficients for specific brain regions in vivo. The detector is straightforward to fabricate and calibrate, is stable in air storage > 9 months, and can be easily installed in an electrophysiology setup, thereby enabling direct measurement of light spread under conditions used in optogenetics experiments.

Configuring the light power emitted from the optical fiber is an essential first step in planning in-vivo optogenetic
experiments. However, diffusion theory, which was adopted for optogenetic research, precluded accurate estimates of
light intensity in the semi-diffusive region where the primary locus of the stimulation is located. We present a 3D Monte
Carlo model that provides an accurate and direct solution for light distribution in this region. Our method directly records
the photon trajectory in the separate volumetric grid planes for the near-source recording efficiency gain, and it
incorporates a 3D brain mesh to support both homogeneous and heterogeneous brain tissue. We investigated the light
emitted from optical fibers in brain tissue in 3D, and we applied the results to design optimal light delivery parameters
for precise optogenetic manipulation by considering the fiber output power, wavelength, fiber-to-target distance, and the
area of neural tissue activation.

To restore vision in patients who lost their photoreceptors due to retinal degeneration, we developed a photovoltaic subretinal prosthesis which converts light into pulsed electric current, stimulating the nearby inner retinal neurons. Visual information is projected onto the retina by video goggles using pulsed near-infrared (~900nm) light. This design avoids the use of bulky electronics and wiring, thereby greatly reducing the surgical complexity. Optical activation of the photovoltaic pixels allows scaling the implants to thousands of electrodes, and multiple modules can be tiled under the retina to expand the visual field.
We found that similarly to normal vision, retinal response to prosthetic stimulation exhibits flicker fusion at high frequencies (>20Hz), adaptation to static images, and non-linear summation of subunits in the receptive fields. Photovoltaic arrays with 70um pixels restored visual acuity up to a single pixel pitch, which is only two times lower than natural acuity in rats. If these results translate to human retina, such implants could restore visual acuity up to 20/250. With eye scanning and perceptual learning, human patients might even cross the 20/200 threshold of legal blindness. In collaboration with Pixium Vision, we are preparing this system (PRIMA) for a clinical trial. To further improve visual acuity, we are developing smaller pixels – down to 40um, and on 3-D interface to improve proximity to the target neurons. Scalability, ease of implantation and tiling of these wireless modules to cover a large visual field, combined with high resolution opens the door to highly functional restoration of sight.

Short infrared laser pulses have many physiological effects on cells including the ability to stimulate action potentials in
neurons. Here we show that short infrared laser pulses can also reversibly block action potentials. Primary rat
hippocampal neurons were transfected with the Optopatch2 plasmid, which contains both a blue-light activated channel
rhodopsin (CheRiff) and a red-light fluorescent membrane voltage reporter (QuasAr2). This optogenetic platform allows
robust stimulation and recording of action potential activity in neurons in a non-contact, low noise manner. For all
experiments, QuasAr2 was imaged continuously on a wide-field fluorescent microscope using a Krypton laser (647 nm)
as the excitation source and an EMCCD camera operating at 1000 Hz to collect emitted fluorescence. A co-aligned
Argon laser (488 nm, 5 ms at 10Hz) provided activation light for CheRiff. A 200 mm fiber delivered infrared light
locally to the target neuron. Reversible action potential block in neurons was observed following a short infrared laser
pulse (0.26-0.96 J/cm2; 1.37-5.01 ms; 1869 nm), with the block persisting for more than 1 s with exposures greater than
0.69 J/cm2. Action potential block was sustained for 30 s with the short infrared laser pulsed at 1-7 Hz. Full recovery of
neuronal activity was observed 5-30s post-infrared exposure. These results indicate that optogenetics provides a robust
platform for the study of action potential block and that short infrared laser pulses can be used for non-contact, reversible
action potential block.

This paper summarizes the results of an EU project called ACTION: ACTive Implant for Optoacoustic Natural sound
enhancement. The project is based on a recent discovery that relatively low levels of pulsed infrared laser light are capable
of triggering activity in hair cells of the partially hearing (hearing impaired) cochlea and vestibule. The aim here is the
development of a self-contained, smart, highly miniaturized system to provide optoacoustic stimuli directly from an array
of miniature light sources in the cochlea. Optoacoustic compound action potentials (oaCAP) are generated by the light
source fully inserted into the unmodified cochlea. Previously, the same could only be achieved with external light sources
connected to a fiber optic light guide. This feat is achieved by integrating custom made VCSEL arrays at a wavelength of
about 1550 nm onto small flexible substrates. The laser light is collimated by a specially designed silicon-based ultra-thin
lens (165 um thick) to get the energy density required for the generation of oaCAP signals. A dramatic miniaturization of
the packaging technology is also required. A long term biocompatible and hermetic sapphire housing with a size of less
than a 1 cubic millimeter and miniature Pt/PtIr feedthroughs is developed, using a low temperature laser assisted process
for sealing. A biofouling thin film protection layer is developed to avoid fibrinogen and cell growth on the system.

Infrared neural modulation (INM) is a label-free method for eliciting neural activity with high spatial selectivity in mammalian models. While there has been an emphasis on INM research towards applications in the peripheral nervous system and the central nervous system (CNS), the biophysical mechanisms by which INM occurs remains largely unresolved. In the rat CNS, INM has been shown to elicit and inhibit neural activity, evoke calcium signals that are dependent on glutamate transients and astrocytes, and modulate inhibitory GABA currents. So far, in vivo experiments have been restricted to layers I and II of the rat cortex which consists mainly of astrocytes, inhibitory neurons, and dendrites from deeper excitatory neurons owing to strong absorption of light in these layers. Deeper cortical layers (III-VI) have vastly different cell type composition, consisting predominantly of excitatory neurons which can be targeted for therapies such as deep brain stimulation. The neural responses to infrared light of deeper cortical cells have not been well defined. Acute thalamocortical brain slices will allow us to analyze the effects of INS on various components of the cortex, including different cortical layers and cell populations. In this study, we present the use of photoablation with an erbium:YAG laser to reduce the thickness of the dead cell zone near the cutting surface of brain slices. This technique will allow for more optical energy to reach living cells, which should contribute the successful transduction of pulsed infrared light to neural activity. In the future, INM-induced neural responses will lead to a finer characterization of the parameter space for the neuromodulation of different cortical cell types and may contribute to understanding the cell populations that are important for allowing optical stimulation of neurons in the CNS.

By combining optical and genetic methods, optogenetics has become a very important tool in neuroscience research for manipulating neuron activities. The rapid development of novel opsins and fluorescent indicators has introduced a large palette of biochemical probes for optogenetic stimulation and cellular imaging, which makes the all-optical neural circuit excitation and neural activity recording possible. Compared to visible-light illumination, two-photon excitation and imaging avoids the crosstalk from optogenetic probes and calcium sensors, and provides for deeper penetration and higher spatial-temporal resolution for single-cell-level precise manipulation. Two-photon interactions frequently necessitate the use of high-power sources with narrow bandwidth outputs. Although tunable sources, such as the titanium-sapphire laser, offer some degree of flexibility, multiple bulky and expensive lasers are required for simultaneous two-photon optogenetic stimulation and calcium imaging. Here, we propose to use fiber-based supercontinuum generation as a broadband coherent light source for two-photon excitation and imaging. A custom-made photonic crystal fiber is pumped by a Yb:KYW laser (1041 nm, 220 fs, 80 MHz) to generate a femtosecond output with a wide range of wavelengths, 900 - 1170 nm, which covers most of the two-photon excitation wavelengths of the molecules used in optogenetics, e.g. C1V1-2A-mCherry and GCaMP6s in our study. A pulse shaper is utilized to modulate the phases of partial wavelengths to tailor the temporal shape of the femtosecond pulse, which manipulates the absorption of optogenetic probes and provides a unique approach for controllable optogenetic excitation. Video-rate calcium imaging results suggest that spectral-temporal programmable supercontinuum pulses provide a powerful tool for neural network activity research.

Many techniques may modulate peripheral nerve activity. Infrared light (IR) can excite or inhibit nerves. Compound action potentials (CAPs) are often measured as an endpoint, focusing on complete block, or overall amplitude reduction. To our knowledge, no standard techniques determine whether CAP sub-components have been modulated. Treatments may alter timing of CAP components as well as blocking them. How can these be distinguished?
We developed a numerical simulation in which extracellularly recorded action potentials were summed, assuming a Gaussian distribution for their onset time. Onset time for sub-populations was delayed (shifting), or amplitudes were reduced to zero (blocking). We demonstrated that area under the rectified curve, divided by the entire duration of the CAP, provided a more stable measure of change than other options (e.g., power). Regions must be selected such that the CAP’s individual components do not shift out of the analysis window. The largest reductions in area under the curve due to shifts were ~55% due to destructive interference, which is likely to be much larger than typically observed experimentally. In contrast, blocking components could reduce the area under the curve to zero.
The analysis was applied to sequential nerve stimulations. At every point, variance of the normalized area was computed. Choosing regions of lowest variance across stimulations defined an objective criterion for boundaries between CAP subcomponents. Analysis was applied to IR effects on CAPs recorded in the pleural-abdominal connective of Aplysia californica and musk shrew vagus. Slower conducting CAP subcomponents were selectively blocked before faster subcomponents.

Recent fcMRI studies examining spontaneous brain activity after stoke have revealed disrupted global patterns of functional connectivity (FC). Interestingly, acute interhemispheric homotopic FC has been shown to be predictive of recovery potential. While substantial indirect evidence also suggests that homotopic brain activity may directly impact recovery, results in humans are extremely varied. A better understanding of how activity within networks functionally-connected to lesioned tissue influences brain plasticity might improve therapeutic strategies. We combine cell-type specific optogenetic targeting with optical intrinsic signal (OIS) imaging to assess the effects of homotopic contralesional activity (specifically in excitatory CamKIIa pyramidal neurons) on FC, cortical remapping, and behavior after stroke. Thirty-one mice were housed in enriched cages for the experiment. OIS imaging was performed before, 1, and 4 weeks after photothrombosis of left forepaw somatosensory cortex (S1fp). On day 1 after stroke, 17 mice were subjected to chronic, intermittent optical stimulation of right S1fp for 10 min, 5 days/week for 4 weeks. New cortical representations of left S1fp appeared in non-stimulated mice at week 1, but not in stimulated mice (p=0.005). Evoked responses were comparable in both groups at week 4 (p=0.57). Homotopic FC between left and right S1fp regions was equally reduced in both groups (p=0.012) at week 1. However, in non-stimulated mice, behavioral performance and FC between right S1fp and left perilesional S1 cortex was significantly higher by 4 weeks compared to stimulated mice (p=0.009). Our results suggest that increased homotopic, contralesional activity in excitatory neurons negatively influences spontaneous recovery following ischemic stroke.

Photodegenerative retinal diseases such as retinitis pigmentosa (RP) and dry age related macular degeneration (dry-
AMD) lead to loss of vision in millions of individuals. Currently, no surgical or medical treatment is available
though optogenetic therapies are in clinical development. Here, we demonstrate vision restoration using Multi-
Characteristics Opsin (MCO1) in animal models with photo-degenerated retina. MCO1 is reliably delivered to
specific retinal cells via intravitreal injection of Adeno-Associated Virus, leading to significant improvement in
visually guided behavior conducted using a radial-arm water maze. The time to reach platform significantly reduced
after delivery of MCO1. Notably, the improvement in visually guided behavior was observed even at light intensity
levels orders of magnitude lower than that required for Channelrhodopsin-2 opsin. Chronic light exposure study
showed that chronic light exposure did not compromise viability of vMCO1-treated retina. Safe virus-mediated
MCO1-delivery has potential for effective gene therapy of diverse retinal degenerations in patients.

Localized, non-invasive cell stimulation has many applications. Here we show the initial proof-of-concept in vitro study
of the photoacoustic cell stimulation approach, which is amenable to high-throughput screening applications. The
proposed method is implemented as follows: 1) the localized excitation using the focused pulsed laser delivery on an
absorptive material placed inside the well containing the cells, 2) cell stimulation by the photoacoustic pressure
generated, and 3) fluorescence quantification of the membrane potential change over time. The preliminary proof-ofconcept
in vitro study is conducted with primary neurons isolated from mouse cerebral cortex. The absorptive rubber
media generates the photoacoustic pressure by the pulsed laser excitation. The experimental results show the feasibility
of photoacoustic cell stimulation approach by indicating the significant membrane potential chance from the
photoacoustically-stimulated primary neurons. Otherwise, the sham control without any photoacoustic stimulation shows
minimal membrane potential change. We envisage that the proposed approach can allow broad strategies for noninvasive
cell stimulation by using the photoacoustic contrasts situated at inside or outside of the body such as external
absorptive materials or intravascularly-injected photoacoustic contrast particles.

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